Hyperleptinemia Contributes to Antipsychotic Drug-Associated Obesity and Metabolic Disorders

Authors

Shangang Zhao
Qian Lin
Wei Xiong
Li Li
Leon Straub
Dinghong Zhang
Rizaldy Zapata
Qingzhang Zhu
Xue-Nan Sun
Zhuzhen Zhang
Jan-Bernd Funcke
Chao Li
Shiuhwei Chen
Yi Zhu
Nisi Jiang
Guannan Li
Ziying Xu
Steven C Wyler
May-Yun Wang
Juli Bai
Xianlin Han
Christine M Kusminski
Ningyan Zhang
Zhiqiang An
Joel K Elmquist
Olivia Osborn
Chen Liu
Philipp E Scherer

Publication Date

11-22-2023

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.ade8460

PMID

37992151

PMCID

PMC11755893

PubMedCentral® Posted Date

1-23-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Mice, Animals, Antipsychotic Agents, Leptin, Obesity, Weight Gain, Metabolic Diseases

Abstract

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.